Management of patients with lymphoma and COVID‐19: Narrative review and evidence‐based practical recommendations

Abstract Patients with hematologic malignancies can be immunocompromized because of their disease, anti‐cancer therapy, and concomitant immunosuppressive treatment. Furthermore, these patients are usually older than 60 years and have comorbidities. For all these reasons they are highly vulnerable to infection with severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) and have an increased risk of developing severe/critical Coronavirus disease 2019 (COVID‐19) compared to the general population. Although COVID‐19 vaccination has proven effective in reducing the incidence of severe/critical disease, vaccinated patients with lymphoma may not be protected as they often fail to develop a sufficient antiviral immune response. There is therefore an urgent need to address the management of patients with lymphoma and COVID‐19 in the setting of the ongoing pandemic. Passive immunization with monoclonal antibodies against SARS‐CoV‐2 is a currently available complementary drug strategy to active vaccination for lymphoma patients, while monoclonal antibodies and antiviral drugs (remdesivir, ritonavir‐boosted nirmatrelvir, and molnupiravir) have proven effective in preventing the progression to severe/critical COVID‐19. In this narrative review we present the most recent data documenting the characteristics and outcomes of patients with concomitant lymphoma and COVID‐19. Our ultimate goal is to provide practice‐oriented guidance in the management of these vulnerable patients from diagnosis to treatment and follow‐up of lymphoma. To this purpose, we will first provide an overview of the main data concerning prognostic factors and fatality rate of lymphoma patients who develop COVID‐19; the outcomes of COVID‐19 vaccination will also be addressed. We will then discuss current COVID‐19 prophylaxis and treatment options for lymphoma patients. Finally, based on the literature and our multidisciplinary experience, we will summarize a set of indications on how to manage patients with lymphoma according to COVID‐19 exposure, level of disease severity and former history of infection, as typically encountered in clinical practice.

Since the outbreak of the COVID-19 pandemic, epidemiological studies worldwide have shown that cancer patients are highly vulnerable to SARS-CoV-2 infection and may be at risk for severe COVID-19. [3][4][5][6][7][8][9][10] Patients with hematologic malignancies appear to have worse COVID-19-related outcomes than those with solid malignancies, but this point has not been conclusively established. 8,11,12 Cancer patients are a vulnerable group for several reasons. They can be immunocompromized because of their disease, anti-cancer therapy, and concomitant immunosuppressive treatment. Furthermore, a large proportion of them are aged >60 years and have comorbidities. 5 With regard to the role of immunosuppression, it should be noted that an attenuated immune system may in fact protect patients against multi-organ injury caused by the excessive inflammatory response that characterizes severe/critical COVID-19. 13,14 Lymphomas are a heterogeneous group of malignant neoplasms of lymphocytes that can affect the lymphatic tissue, bone marrow, and any other body organ. 15,16 Traditionally, they are divided into Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL), with the latter accounting for approximately 90% of all lymphomas. 15 NHL are often treated with chemotherapy with or without the addition of monoclonal antibodies against CD20-positive B lymphocytes, inducers of T lymphocyte depletion, or immunomodulators. As seen for other diseases, the COVID-19 pandemic has introduced significant changes in oncologic practice, with a substantial burden on patients and health care providers and the potential worsening of patient outcomes. 8 In addition, although COVID-19 vaccination has proven effective in reducing the incidence of severe COVID-19 in the general population, [17][18][19][20] vaccinated patients with lymphoma may not be protected as they often fail to develop a sufficient antiviral immune response. [21][22][23] Also, as we have learned from the omicron variant, new SARS-CoV-2 strains may be only partially neutralized by existing vaccines. 21 Lymphoma patients are therefore at high risk of breakthrough SARS-CoV-2 infection and indications on how to manage this vulnerable group are urgently needed. 24 Alternative prophylactic strategies, including passive immunization with monoclonal antibodies to the spike protein of SARS-CoV-2, [25][26][27][28][29][30] and treatment of mild or moderate COVID-19 with antiviral agents [31][32][33] need to be explored in lymphoma patients. In addition, programs of booster vaccinations need to be implemented as the emerging data on additional vaccine doses in patients with no seroconversion after the first vaccination cycle are promising. 34 In this narrative review we present the most recent data documenting the characteristics and outcomes of patients with concomitant lymphoma and COVID-19; our objective is to provide evidence-based guidance in the management of these vulnerable patients from diagnosis to treatment and follow-up. To this purpose, we will first report the main data concerning prognostic factors and mortality rates of lymphoma patients who develop COVID-19; the outcomes of COVID-19 vaccination will also be addressed. We will then discuss current treatment options for SARS-CoV-2-infected subjects at high risk of progressing to severe/critical disease.
Finally, based on the literature and our multidisciplinary experience, we will provide practical guidance on how to manage patients with lymphoma in the setting of ongoing COVID-19 pandemic.

| METHODS
We searched PubMed with the terms "lymphoma AND (COVID-19 OR SARS-CoV-2)" for any type of article published in English up to 27 May 2022. Retrieved articles were screened based on their title and abstracts. Articles of potential interest were further selected by giving the preference to well-designed studies, large patient populations, and systematic reviews or meta-analyses of the literature.  37 The model assigns a total score from 0 to 5 based on the presence or absence of the four variables, and classifies risk into three levels, low (total score 0-1), intermediate (2)(3), and high (4-5).
As the model uses easily available variables, its implementation in clinical practice should be straightforward. follicular lymphoma on maintenance with anti-CD20 therapy following remission, a lower mortality (31%) was reported compared to chemotherapy plus anti-CD20 therapy (47%), or chemotherapy alone (44%). 6 Lamure et al. found no association between anti-CD20 therapy and increased mortality; an increase in mortality was seen with bendamustine in the high-risk group of patients with relapsed/ refractory lymphoma. 35 Regalado-Artamendi investigated whether the persistence of SARS-CoV-2 infection was related to antineoplastic therapy, anti-CD20 therapy in particular; 6 months after the onset of infection, the proportion of patients treated with anti-CD20 therapy was similar between the group with a negative SARS-CoV-2 test and the group with a persistently positive test. 36 In the lymphoma population analyzed by Visco and colleagues, 33% had recent treatment (≤6 months) and 24% had been treated >6 months before COVID-19 diagnosis. 37 These treatments, including anti-CD20 therapy and bendamustine, did not appear to worsen mortality rates.
Based on these preliminary findings, a common notion is that discontinuing effective antineoplastic treatment may not be justified in lymphoma patients in the pandemic. 6 This notion is reflected in the current guidelines for the treatment of patients with hematological malignancies during the COVID-19 pandemic. 24 It should be noted, however, that the impact of previous antineoplastic therapy on

| COVID-19 course in vaccinated lymphoma patients
Data documenting the outcomes of patients with lymphoma who have been vaccinated against SARS-CoV-2 are lacking. Evidence from studies in cancer patients suggests that those who develop COVID-19 following full vaccination continue to be at risk of substantial comorbidity and death. 43,44 Risk factors for developing COVID-19 following vaccination include older age, single vaccine dose without previous COVID-19, and anti-CD20 therapy in the previous 3 months. 44 In January 2021, the EPICOVIDEHA registry started to collect prospectively the data of patients with hematologic malignancies who had been vaccinated against COVID-19. 45 The preliminary data of 113 patients who developed COVID-19 following partial or complete vaccination have shown that the majority of these patients had lymphoproliferative malignancies (>80%), were male (61.1%) and were aged >50 years (85.8%). 45  developed before or after vaccination. 34 The study found that in vaccinated individuals the rates of critical disease (10% vs. 33%, p = 0.0242) and hospitalization (17% vs. 50%, p = 0.0024) were significantly lower and the median disease duration was significantly shorter (16 vs. 22 days, p = 0.0094) than in unvaccinated individuals. 34 Overall, these preliminary results suggest that vaccination reduces the mortality rate compared to the pre-vaccination period.
However, they also show that patients with hematologic malignancies continue to be vulnerable.

| Long-term consequences of COVID-19
It is increasingly recognized that a proportion of patients who have

| Immunization following SARS-CoV-2 infection
Humoral responses to SARS-CoV-2 infection have been shown to be less pronounced and slower in individuals with hematologic conditions compared to the general population. 23 In a retrospective study within the ITA-HEMA-COV project evaluating the humoral immune response to SARS-CoV-2 in 237 patients with hematologic malignancies (51.1% with lymphoid neoplasms) who had been exposed to SARS-CoV-2, 31% of patients were serologically negative. 42 Chemoimmunotherapy was significantly associated with lower rates of seroconversion (OR 3.42, 95% CI 1.04-11.21; p = 0.04). Notably, this association persisted up to 6 months following therapy discontinuation. Based on these observations and on the experience with other vaccines, 47 it can be expected that many patients with lymphoma will fail to mount an adequate response to COVID-19.

| Vaccination
Growing evidence from studies of COVID-19 vaccination shows that patients with hematologic malignancies, and especially those on PASSAMONTI ET AL.

| Booster vaccination
The efficacy of booster COVID-19 vaccination in lymphoma patients also needs to be addressed. Evidence from studies in cancer patients suggests that those who did not achieve seroconversion after complete vaccination may benefit from an additional dose of vaccine. 34

| PROPHYLAXIS AND THERAPEUTIC OPTIONS FOR SUBJECTS AT HIGH RISK OF COVID-19 PROGRESSION
Passive immunization with monoclonal antibodies against SARS-CoV-2 is an available strategy complementary to vaccination for patients who are unlikely to generate neutralizing antibodies. Antiviral drugs and monoclonal antibodies are valid treatment options for preventing the development of severe-critical COVID-19 in vulnerable patients with mild-moderate disease. ductions ranging from 70% to 85%. 26,68 As for the safety of monoclonal antibodies, no particular safety issues were reported in the pivotal trials, which consistently showed no differences in the adverse event profile of active treatment and placebo. [26][27][28]30,68 The phase 3 PROVENT trial in patients with an increased risk of responding inadequately to vaccination, an increased risk of exposure to SARS-CoV-2, or both, found that patients receiving tixagevimab  active against all omicron subvariants but it is currently available in US only. 76 The reader is referred to the following databases for updated information on the activities of current vaccines, monoclonal antibodies and antivirals on VOCs: https://opendata.ncats.nih.gov/ variant/activity and https://covdb.stanford.edu/susceptibility-data/

| Antiviral agents
Currently three antiviral agents are available for the treatment of  hematologic malignancies have lower seroconversion rates than the general population also following natural immunization. 42 With regard to the management of lymphoma, the ESMO/EHA guidelines distinguish between indolent and aggressive lymphoma. When indicated, antineoplastic treatment should be given as recommended, "without compromising efficacy of treatment". 24 At the same time, whenever possible, unvaccinated patients should receive COVID-19 vaccination (at least the first dose) before initiating antineoplastic treatment. In case of newly diagnosed or relapsing aggressive lymphoma, however, treatment has the priority over COVID-19 vaccination and should not be postponed. 24 Table 2  For daily clinical practice, given the availability of vaccination, tixagevimab-cilgavimab as pre-exposure prophylaxis, and antivirals and/or monoclonal antibodies, we recommend to maintain the indication for less immunosuppressive anti-CD20 agents for follicular lymphomas, as local practice in the pre-pandemic era.
The benefits of these strategies need to be further evaluated. To this purpose, the collection of real-world data documenting the use monoclonal antibodies and antiviral agents in lymphoma patients in clinical practice should be encouraged.